Huntington's Disease is one member of a family of neurodegenerative diseases caused by expansion of polyglutamine (poly-Q) tracts in otherwise unrelated proteins. Proteins containing more than 40 consecutive glutamine residues form intracellular aggregates comprised of the disease-causing protein and other glutamine rich cellular proteins. While the poly-Q containing proteins are widely expressed, cellular toxicity is localized primarily to the central nervous system. The mechanism of poly-Q mediated toxicity is not fully understood. Proposed mechanisms include direct toxicity of protein aggregates and depletion of glutamine-rich transcription factors required for neuronal cell health. We propose to develop a multiplexed drug discovery assay in Caenorhabditis elegans for poly-Q mediated neurodegenerative disease. This assay will monitor neuronal expression of two fluorescent reporter proteins simultaneously and will thus allow identification of useful lead compounds that might be missed in assays focused on a single parameter. The assay will allow drug discovery researchers to define a hit as a compound affecting either one or both of the fluorescent reporters thereby increasing the specificity of the assay. The fluorescent reporters will model: 1) polyglutaminated disease causing proteins, and 2) co-agglutination of glutamine-rich transcription factors. Our overall Phase I and II goal is a validated method of drug discovery by in vivo screening of disease models that will be licensed to a biopharmaceutical partner. Introduction of the assay into the drug discovery lab is expected to lead to identification of novel bioactive compounds that are suitable for further preclinical and clinical development. [unreadable] [unreadable]